scholarly journals DDIT4 Novel Mutations in Pancreatic Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Fadian Ding ◽  
Xiaoping Hong ◽  
Xiangqun Fan ◽  
Shirong Huang ◽  
Wei Lian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Gene Mutation ◽  
Dna Sequences ◽  
Gene Mutations ◽  
Ductal Adenocarcinoma ◽  
Stable Gene ◽  
Nuclear Staining ◽  
Clinical Value ◽  
Polymerase Chain ◽  
Cancer Tissues

Pancreatic cancer is one of the most common malignancies worldwide. This study is aimed at searching the possible genetic mutations and the value of novel gene mutation in the DNA damage-inducible transcript 4 (DDIT4) and signaling pathway in pancreatic cancer. Polymerase chain reaction (PCR) was performed to amplify the DNA sequences of DDIT4 from patients with pancreatic ductal adenocarcinoma. In addition, we used IHC to detect the expression level of DDIT4 in patients with pancreatic cancer in different types of gene mutation. Double-labeled immunofluorescence was employed to explore the expression levels of DDIT4/LC3 and their potential correlation. Our work indicated the two novel stable gene mutations in DDIT4 mRNA 3 ′ -untranslated region (m.990 U>A and m.1246 C>U). Thirteen samples were found to have mutation in the DDIT4 3 ′ -untranslated regions (UTR). To further verify the influence of gene mutation on protein expression, we performed immunohistochemistry on different gene mutation types, and we found a correlation between DDIT4 expression and gene mutation, which is accompanied by nuclear staining deepening. In order to further discuss the clinical value of DDIT4 gene mutation, immunofluorescence suggested that the expression of DDIT4 colocated with LC3; thus, we speculated that DDIT4 mutation may be involved in autophagy in pancreatic cancer cell. In this study, we found mutation in the 3 ′ -UTR region of DDIT4, which may be associated with DDIT4 expression and tumor autophagy in pancreatic cancer tissues.

Clonal Evolution and Devolution Following Chemotherapy in Adult Acute Myelogenous Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2487-2487
Author(s):  
Brian Parkin ◽  
Peter Ouillette ◽  
Yifeng Li ◽  
Cheng Li ◽  
Kerby Shedden ◽  
...  
Keyword(s):  
Complete Remission ◽  
Gene Mutation ◽  
Induction Chemotherapy ◽  
Acute Myelogenous Leukemia ◽  
Conflicts Of Interest ◽  
Gene Mutations ◽  
Myelogenous Leukemia ◽  
Stable Gene ◽  
Paired Data ◽  
Acute Myelogenous

Abstract Abstract 2487 Introduction: Despite significant advances in the understanding of the biology of adult acute myelogenous leukemia (AML), overall survival remains poor due chiefly to the high rate of relapse after achieving complete remission as well as primary failure of induction chemotherapy. Efforts to further unravel the mechanisms leading to relapse and primary refractory disease are critical in order to guide the development of effective and durable treatment strategies for AML. To that end, this study seeks to elucidate the clonal relationship of AML in various disease phases. Methods: We employed SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients that achieved complete remission with chemotherapy and subsequently relapsed (median remission duration 272 days [range 25 – 1249 days]) and 11 sample pairs from patients with persistent disease following induction chemotherapy. AML cell samples were isolated with a Ficoll gradient, negatively selected using Miltenyi microbead columns, and then further purified with flow cytometric cell sorting. Processed DNA isolated from highly purified AML blasts and paired buccal DNA was hybridized to Affymetrix SNP 6.0 arrays. aCNA were visually identified using the dChip program in paired data displays and corroborated by algorithmic lesion scoring, and cnLOH was detected using internally developed software. In addition, 11 genes known to be recurrently mutated in AML (CEBPA, DNMT3A, IDH1, IDH2, RUNX1, BCORL1, NPM1, NRAS, KRAS, FLT3 and TP53) were resequenced in all 39 presentation samples to identify somatically acquired mutations. Genes found mutated in individual AML cases were subsequently tested for the persistence of the mutation in paired samples. Results: For the 28 paired specimens in the relapsed cohort, comparison of aCNA and cnLOH occurrences, gene mutation patterns and karyotypes revealed 6 cases that carried no aCNA/cnLOH at either presentation or relapse, but at presentation carried at least 1 gene mutation, all of which but one were stable in relapse (1 case lost a RUNX1 mutation but carried a t(8;21) in both disease stages); 11 cases that were characterized by the presence of aCNA/cnLOH at presentation, of which 55% (6 of 11) gained additional aCNA/cnLOH at relapse; 6 cases without aCNA/cnLOH at presentation that gained aCNA/cnLOH at relapse, of which 2 concurrently lost a FLT3-ITD or CEPBA mutation; and 5 cases that carried no informative genomic events. For the 11 paired specimens in the persistent AML cohort, the same comparison revealed 2 cases without aCNA/cnLOH before or after chemotherapy and stable gene mutations; 5 cases with aCNA/cnLOH at presentation that carried the same genomic lesions and gene mutations before and after chemotherapy; 3 cases with aCNA/cnLOH present at enrollment that lost some but not all of these aCNA/cnLOH and gained none after initial induction therapy; and 1 additional case that lost a FLT3-ITD. Comparative analysis of these patterns demonstrates that relapsed AML invariably represents reemergence or evolution of an antecedent clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered at least two coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant. Conclusion: This detailed genomic analysis supports the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research. Disclosures: No relevant conflicts of interest to declare.

Homologous recombination repair gene mutations in Chinese pancreatic ductal adenocarcinoma patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16234-e16234
Author(s):  
Nengwen Ke ◽  
Maolin Yan ◽  
Xu Che ◽  
Yu Cheng ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Homologous Recombination ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Checkpoint Inhibitors ◽  
Gene Mutations ◽  
Ductal Adenocarcinoma ◽  
Homologous Recombination Repair ◽  
Common Mutation ◽  
Wild Type ◽  
Recombination Repair

e16234 Background: Pancreatic cancer (PC) is a highly malignant tumor with poor prognosis. Among them, pancreatic ductal adenocarcinoma (PDAC) accounts for 80-90% of pancreatic cancer. While, the treatment of PDAC has always been a clinical challenge. PDAC with mutations in homologous recombination repair (HRR) genes such as BRCA are particularly sensitive to platinum agents. The POLO study has shown that Olaparib was efficient and well-tolerated as maintenance therapy in patients with germline BRCA1/2 mutation and a metastatic PDAC controlled after a platinum-based induction chemotherapy. However, investigation of prevalence of HRR gene mutations in Chinese PDAC patients need to be well defined. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from PDAC patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations and tumor mutational burden (TMB) values were assessed. The association of HRR gene mutations with TMB was assessed. The testing was carried out by OrigiMed (Shanghai, China) witch a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Using targeted capture genomic sequencing, we assessed 98 PDAC patients for germline and somatic loss-of-function mutations in 14 genes, including BRCA1, BRCA2, and 12 other genes in the HR pathway. Results: In total, 98 PDAC patients were recruited including 48 females and 50 males with a median age of 58 (range 35-84). The most frequently mutated genes were KRAS (94%), TP53 (74%), CDKN2A (36%), SMAD4 (27%), GATA6 (9%) and ATM (5%). Mutation rates varied in pancreatic cancer signaling pathway: WNT (35.71%), PI3K (11.22%), HRR (11.22%), NOTCH (3.06%), FGF (2.04%). 2.04% (2/98) patients had high TMB (defined as ≥10 muts/Mb) with a median of 2.2 muts/Mb (0-47 mus/Mb). 34.69% (34/98) of the patients had one or more actionable genetic mutations. We identified that 11.2% (11/98) patients had at least one mutation in HRR genes. The most frequently mutated HRR genes were ATM (50%), BRCA1 (16.7%), BRCA2 (25%) and PALB2 (8.3%). The most common mutation type in HRR-related gene was truncation (75%, 9/12). HRR-related germline mutations in BRCA (71.43%, 5/7), ATM (28.57%, 2/7) were detected in seven patients, six of them with cancer related family history. We confirmed that patients with HRR mutations were younger than wild type HRR (52.6 years vs. 59.3 years, p < 0. 05). We demonstrated that patients with HRR mutations had a significantly higher TMB than patients with wild type HRR (median TMB: 3.4 vs. 1.8 muts/Mb, p < 0. 05). Conclusions: HRR gene alterations occurred in 11.2% of Chinese PDAC patients HRR pathway alterations are relatively frequent in PDAC patients and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.

scholarly journals Comprehensive Analysis of the Transcriptional Expressions and Prognostic Value of S100A Family in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Hong-Bin Li ◽  
Jian-Li Wang ◽  
Xiao-Dong Jin ◽  
Lei Zhao ◽  
Hui-Li Ye ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Prognostic Value ◽  
Pancreatic Cancer Cell ◽  
Expression Patterns ◽  
Ductal Adenocarcinoma ◽  
Tissue Samples ◽  
Cancer Types ◽  
Cancer Tissues ◽  
Refractory Malignancy

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory malignancy with poor prognosis. It is urgent to identify novel and valid biomarkers to predict the progress and prognosis of PDAC. The S100A family have been identified as being involved in cell proliferation, migration and differentiation progression of various cancer types. However, the expression patterns and prognostic values of S100As in PDAC remain to be analyzed. Methods We investigated the transcriptional expressions, methylation level and prognostic value of S100As in PDAC patients from the Oncomine, GEPIA2, Linkedomics, and cBioPortal databases. Real-time PCR was used to detect the expressions of S100A2/4/6/10/14/16 in four pancreatic cancer cell lines and pancreatic cancer tissues from PDAC patients undergoing surgery. To verify the results further, immunohistochemistry was used to measure the expression of S100A2/4/6/10/14/16 in 43 PDAC patients’ tissue samples. The drug relations of S100As were also analyzed by using Drugbank. Results The results suggested that, the expression levels of S100A2/4/6/10/14/16 were elevated to PDAC tissues than in normal pancreatic tissues, and the promoter methylation levels of S100A S100A2/4/6/10/14/16 in PDAC (n = 10) were lower compared with normal tissue (n = 184) (P < 0.05). In addition, their expressions were negatively correlated with PDAC patient survival. Conclusions Taken together, these results suggest that S100A2/4/6/10/14/16 might be served as prognostic biomarkers for survivals of PDAC patients.

scholarly journals Comprehensive analysis of the transcriptional expressions and prognostic value of S100A family in pancreatic ductal adenocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hong-Bin Li ◽  
Jian-Li Wang ◽  
Xiao-Dong Jin ◽  
Lei Zhao ◽  
Hui-Li Ye ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Prognostic Value ◽  
Expression Patterns ◽  
Ductal Adenocarcinoma ◽  
Tissue Samples ◽  
Cancer Types ◽  
Cancer Tissues ◽  
Drugbank Database ◽  
Refractory Malignancy

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory malignancy with poor prognosis. It is urgent to identify novel and valid biomarkers to predict the progress and prognosis of PDAC. The S100A family have been identified as being involved in cell proliferation, migration and differentiation progression of various cancer types. However, the expression patterns and prognostic values of S100As in PDAC remain to be analyzed. Methods We investigated the transcriptional expressions, methylation level and prognostic value of S100As in PDAC patients from the Oncomine, GEPIA2, Linkedomics and cBioPortal databases. Real-time PCR was used to detect the expressions of S100A2/4/6/10/14/16 in four pancreatic cancer cell lines and pancreatic cancer tissues from PDAC patients undergoing surgery. To verify the results further, immunohistochemistry was used to measure the expression of S100A2/4/6/10/14/16 in 43 PDAC patients’ tissue samples. The drug relations of S100As were analyzed by using the Drugbank database. Results The results suggested that, the expression levels of S100A2/4/6/10/14/16 were elevated to PDAC tissues than in normal pancreatic tissues, and the promoter methylation levels of S100A S100A2/4/6/10/14/16 in PDAC (n = 10) were lower compared with normal tissue (n = 184) (P < 0.05). In addition, their expressions were negatively correlated with PDAC patient survival. Conclusions Taken together, these results suggest that S100A2/4/6/10/14/16 might be served as prognostic biomarkers for survivals of PDAC patients.

A model for molecular screening of newborns: simultaneous detection of Duchenne/Becker muscular dystrophies and cystic fibrosis

1990 ◽  
Vol 36 (10) ◽  
pp. 1756-1759 ◽  
Author(s):  
T W Prior ◽  
W E Highsmith ◽  
K J Friedman ◽  
T R Perry ◽  
G Scheuerbrandt ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dna Sequences ◽  
Simultaneous Detection ◽  
Gene Mutations ◽  
Becker Muscular Dystrophy ◽  
Chain Reaction ◽  
Screening Programs ◽  
Biochemical Assays ◽  
Allele Specific ◽  
Polymerase Chain

Abstract Gene mutations responsible for the majority of Duchenne/Becker muscular dystrophy (DMD/BMD) and cystic fibrosis (CF) chromosomes have been identified. We describe a DNA-based strategy, rather than the traditional biochemical assays, for screening newborns. DNA sequences spanning the CF mutation and several DMD/BMD deletion-prone exons are amplified simultaneously via a multiplex polymerase chain reaction. The gel is visually inspected for DMD/BMD deletions and then blotted and hybridized with allele-specific oligonucleotides to determine the presence or absence of the CF mutation. We determined that blood spots provide sufficient DNA for the molecular analysis, so the procedure can be used in screening programs of newborns.

Lymphoepithelioma-like Carcinoma of the Uterine Cervix

2002 ◽  
Vol 126 (12) ◽  
pp. 1501-1505 ◽  
Author(s):  
Miguel A. Martorell ◽  
Jose M. Julian ◽  
Consuelo Calabuig ◽  
JoséA. García-García ◽  
Ana Pérez-Vallés
Keyword(s):  
Polymerase Chain Reaction ◽  
Human Papillomavirus ◽  
Dna Sequences ◽  
Uterine Cervix ◽  
Simian Virus 40 ◽  
Polymerase Chain Reaction Analysis ◽  
Simian Virus ◽  
Nuclear Staining ◽  
Chain Reaction ◽  
Polymerase Chain

Abstract Context.—It has been proposed that Epstein-Barr virus (EBV) plays a role in the etiology of lymphoepithelioma-like carcinoma (LELC) in diverse anatomic locations. In contrast to Asian women, Western women have a low prevalence of LELC of the uterine cervix, and EBV genomes have not been identified. Objective.—To assess the presence of EBV in LELC of the uterine cervix in 4 white Western women. Design.—We collected 4 cases of LELC of the uterine cervix between 1990 and 2000. We performed histologic and immunohistochemical analyses of formalin-fixed, paraffin-embedded tumor samples. We amplified tumor DNA with polymerase chain reaction to detect EBV, human papillomavirus, and simian virus 40 DNAs. Results.—Immunohistochemically, tumor cells were positive for cytokeratins and showed strong expression of p53 and MIB-1. Staining for the oncoprotein c-Erb-B2 was focally positive, and staining for Bcl-2 and progesterone receptors was negative. Only one case showed focal nuclear staining for estrogen receptors. All cases had a dense infiltrate of mature lymphocytes expressing T-cell antigens CD45RO, CD3, and CD8. Polymerase chain reaction analysis did not detect EBV, human papillomavirus, or simian virus 40 DNA sequences in any of the 4 cases. One case had positive serologic results for anti-EBV antibodies, indicating a mild or chronic infection. Conclusions.—LELC of the uterine cervix shows the immunohistochemical profile of an aggressive tumor in spite of its good prognosis, in which CD8 cytotoxic suppressor lymphocytes could play an important role. Based on our results, the role of EBV, human papillomavirus, or simian virus 40 in the pathogenesis of LELC of the uterine cervix in Western women remains unclear.

The mutational landscape of the adjacent paracancerous tissues confirmed the safe margin of 2-5cm in colorectal cancer resection.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16060-e16060
Author(s):  
Jin Gu ◽  
Jianfei Yao ◽  
Lele Song ◽  
Dandan Huang ◽  
Zhaoya Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Driver Gene ◽  
Molecular Evidence ◽  
Mutational Landscape ◽  
Normal Tissues ◽  
Colorectal Cancer Resection ◽  
Whole Exome ◽  
Cancer Tissues

e16060 Background: Margin of 2-5cm is regarded as the safe margin in surgical resection of colorectal cancer (CRC) by macroscopic pathological examinations. However, whether 2-5cm is safe has never been verified by molecular evidence. Methods: We systematically analyzed the mutational profile of 35 CRC tissues and paired adjacent paracancerous tissues 2-3cm and 5cm adjacent to the cancer margin by whole-exome sequencing. Results: The number of SNV/INDEL mutations in the adjacent 2-3cm and 5cm tissues was much less than that in cancer. The number of common SNV/INDEL mutations between cancer and the adjacent tissues ranged from 0 to 2. Although TP53, APC and KRAS SNV/INDEL mutations exhibited the highest frequency in CRC, the APC SNV/INDEL mutations were observed in only one adjacent 5cm tissue, and no TP53 or KRAS SNV/INDEL mutations were observed in any adjacent tissues. We further determined the potential driver gene mutations in adjacent tissues by searching databases including COSMIC CGC, IntOGen, OncoKB, TCGA and Vogelstein databases. A certain mutation was determined as a driver gene mutation if all five databases predict it to be a driver gene mutation. As a result, 9 SNV/INDEL driver gene mutations (1 ATM, 1 BRCA1, 1 BRCA2, 1 MET, 1 NF1, 3 PTEN and 1 STAG2 mutations) were found in the adjacent 2-3cm group, and 9 SNV/INDEL driver gene mutations (1 APC, 1 ARID1A, 1 FBXW7, 3 PTEN, 2 STAG2 and 1 BRCA2 mutations) were found in the adjacent 5cm group. No common SNV/INDEL driver gene mutations were found between cancer tissues and the paired 2-3cm or 5cm tissues, suggesting the driver gene mutations predicted in adjacent normal tissues may not be cancer-relevant. Conclusions: We established the mutational landscape of the adjacent 2-3cm and 5cm tissues to CRC, and found almost no key driver gene SNV/INDEL mutations in adjacent tissues. No common SNV/INDEL driver gene mutations were found between cancer and the adjacent tissues, supporting a safe resection with a margin at 2 to 5cm.

scholarly journals Comprehensive analysis of the transcriptional expressions and prognostic value of S100A family in pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Hongbin Li ◽  
Jianli Wang ◽  
Xiaodong Jin ◽  
Lei Zhao ◽  
Huili Ye ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Prognostic Value ◽  
Pancreatic Cancer Cell ◽  
Expression Patterns ◽  
Ductal Adenocarcinoma ◽  
Tissue Samples ◽  
Cancer Types ◽  
Cancer Tissues ◽  
Refractory Malignancy

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory malignancy with poor prognosis. It is urgent to identify novel and valid biomarkers to predict the progress and prognosis of PDAC. The S100A family have been identified as being involved in cell proliferation, migration and differentiation progression of various cancer types. However, the expression patterns and prognostic values of S100As in PDAC remain to be analyzed. Methods We investigated the transcriptional expressions, methylation level and prognostic value of S100As in PDAC patients from the Oncomine, GEPIA2, Linkedomics, and cBioPortal databases. Real-time PCR was used to detect the expressions of S100A2/4/6/10/14/16 in four pancreatic cancer cell lines and pancreatic cancer tissues from PDAC patients undergoing surgery. To verify the results further, immunohistochemistry was used to measure the expression of S100A2/4/6/10/14/16 in 43 PDAC patients’ tissue samples. The drug relations of S100As were also analyzed by using Drugbank. Results The results suggested that, the expression levels of S100A2/4/6/10/14/16 were elevated to PDAC tissues than in normal pancreatic tissues, and the promoter methylation levels of S100A S100A2/4/6/10/14/16 in PDAC (n = 10) were lower compared with normal tissue (n = 184) (P < 0.05). In addition, their expressions were negatively correlated with PDAC patient survival. Conclusions Taken together, these results suggest that S100A2/4/6/10/14/16 might be served as prognostic biomarkers for survivals of PDAC patients.

scholarly journals Chylous Ascites, Unusual Association with Ductal Pancreatic Adenocarcinoma with Plasmacytoid Morphology: A Case Report and Literature Review

2021 ◽  
Vol 07 (03) ◽  
pp. e158-e162
Author(s):  
Catalin Bogdan Satala ◽  
Ioan Jung ◽  
Tivadar Jr. Bara ◽  
Vlad Tudorache ◽  
Simona Gurzu
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Surgical Intervention ◽  
Chylous Ascites ◽  
Distal Portion ◽  
Ductal Adenocarcinoma ◽  
Lymph Vessels ◽  
Lymphangiosis Carcinomatosa ◽  
Ductal Pancreatic Adenocarcinoma ◽  
Tumor Emboli

AbstractChylous ascites represents a relatively uncommon condition. In this paper, we present a case of chyloperitoneum associated with pancreatic ductal adenocarcinoma (PDAC) and a review of literature regarding chylous ascites. A 76-year-old male patient was admitted in emergency department with acute abdomen. A pancreatic cancer was suspected. Subtotal spleno-pancreatectomy, for a nodular mass infiltrating the mild and distal portion of the pancreas, was necessary. During surgical intervention in the peritoneal cavity, a moderate quantity of whitish and thick consistency fluid with milk-like appearance was observed to be accumulated. After examination of the fluid, chyloperitoneum was diagnosed. The histologic examination showed a PDAC, with multiple emboli in lymph vessels, with tumor cells with plasmacytoid morphology, diagnosed as lymphangiosis carcinomatosa. The patient died at 3 weeks after surgical intervention. In patients with pancreatic cancer and chylous ascites, suspicion of tumor-related blockage of the lymphatic flow should be suspected. Prognosis of PDAC should be evaluated not only based on the number of lymph node metastases, but also considering the number of lymph vessels with tumor emboli and the architecture of tumor cells. This is the first reported case of a PDAC with plasmacytoid morphology of lymphangiosis carcinomatosa.

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